Chronic venous leg ulcers (CVLU) pose significant health and economic burdens due to their high prevalence and recurrence rates. Innovative approaches to improve the treatment of CVLU are needed because current strategies involving topical therapies are often ineffective. The pathogenesis of CVLU involves high numbers of activated polymorphonuclear leukocytes (PMN) that secrete excessive amounts of proteases that cause tissue damage and persistent inflammation in the wound bed. Emergent evidence indicates that metabolism of long- chain omega-3 (n-3) eicosapentaenoic (EPA) and docosahexaenoic (DHA) polyunsaturated fatty acids (PUFA), the bioactive components of fish oil, produce lipid mediators, such as resolvins and protectins, which have counter-regulatory effects on PMN recruitment and activity. In animal models of inflammatory disease, these lipid mediators inhibit PMN migration to inflamed sites and reduce cell synthesis and secretion of proinflammatory cytokines that are involved in recruiting and activating PMN. However, there have been no studies examining the effects of EPA+DHA-derived lipid mediators on PMN associated with the persistent inflammation in CVLU. Furthermore, n-3 EPA/DHA dietary intake in the U.S. is considerably lower than recommended and the majority of EPA/DHA body stores are obtained from the diet. Based on these findings, our organizing hypothesis is that oral supplementation of EPA+DHA intake will improve healing of CVLU. The purpose of this R21 is to test three fundamental corollaries of this organizing hypothesis in a double-blind, randomized, experimental design on CVLU patients, randomized to two groups: (I) 56 days of oral supplementation with 2.5 g/d of EPA + 0.5 g/d of DHA and (II) 56 days of supplementation with vehicle (mineral oil). The corollaries of the organizing hypothesis are that: 1) the EPA+DHA supplemented group will have higher levels of EPA+DHA-derived lipid mediators and lower levels of proinflammatory cytokines (IL-12, IL-6 and TNF1) in CVLU wound fluid at 28 and 56 days compared to the Control Group; 2) the EPA+DHA supplemented group will have lower counts of PMN and lower levels of PMN-derived proteases (matrix metalloproteinase-8 and neutrophil elastase) in CVLU wound fluid at 28 and 56 days compared to the Control Group; and 3) the EPA+DHA supplemented group will have greater increases in re-epithelialization at 28 and 56 days, which will be inversely related to PMN activity in the wound bed. The findings from the proposed experiments will impact the care of persons with CVLU by increasing our understanding of EPA+DHA-derived lipid mediators that influence wound healing and PMN function, and may lead to an innovative, systemic approach to augment the treatment of nonhealing or recurrent CVLU. If the three corollaries of our organizing hypothesis are supported, a full scale clinical trial evaluating the effects of EPA+DHA supplementation on cellular and molecular mechanisms of wound healing in CVLU patients will be proposed.